The largest US cancer health disparity exists in prostate cancer with African-American men having the highest incidence and mortality rates (5
). This disparity has been widely studied and has been attributed to differences in insurance status and medical care, tumor growth rates and disease aggressiveness, location and histopathological variables of the tumor and genetic predisposition (22
). There is evidence from clinical studies that prostate cancer outcomes are similar for African-American and European-American men when the disease is organ-confined (90
), but African-Americans appear to have worse outcomes when the disease is advanced (22
Prostate tumors tend to develop earlier as a clinical disease in African-American men than in other men (22
). It is recommended that African-American men are screened for prostate cancer starting at age 45, instead of age 50 as recommended for other men, in an attempt to increase early detection of the disease in this population (22
). As a result of these efforts, 40- to 49-year-old African-American men are now more likely to have a PSA test than European-American men in this age group (140
). Although substantial progress has been made in increasing the use of PSA testing among African-American men across all age groups (140
), we still continue to see an almost unchanged disparity in the prostate cancer mortality between these men and European-American men.
The US is not the only geographical location with a higher disease incidence, an earlier disease onset, and an increased aggressiveness of prostate cancer in men of African ancestry. Rather, research in the Caribbean, South America and United Kingdom found an excessive disease burden in men of African ancestry when compared with men from other population groups (27
). Additional studies in West and Central Africa revealed a high prevalence of prostate tumors in men visiting hospitals in Nigeria, Senegal, Cameroon and Kenya (147
). Importantly, the authors of these studies noted that the prostate cancer incidence in these areas may have been grossly underestimated. Since many of the African men with prostate tumors have an advanced disease at diagnosis, screening for early detection of prostate tumors in parts of Africa would probably save many lives as well as shed light on the factual incidence rate for this disease in African populations.
It is generally accepted that modifiable risk factors account for the majority of prostate cancers globally (151
), although recent findings from genetic research suggest a significant influence of common genetic variations in disease development (12
). A literature review of exposure differences in modifiable risk factors between African-Americans and European-Americans found only modest differences between these population groups with respect to prostate cancer development (152
). One such risk factor that has been widely studied is dietary patterns among African-Americans and European-Americans (153
). African-Americans were found to have a lower overall fruit and vegetable consumption, with the caveat that they may consume a higher frequency of specific types of fruits and vegetables (e.g. cruciferous vegetables) that are considered to be protective against cancer (154
). In addition to the assessment of fruit and vegetable consumption, meat and animal fat intake have been identified as a candidate prostate cancer risk factor for African-Americans in two studies (156
). It is well established that African-Americans have higher rates of vitamin D deficiency than European-Americans. Both cell culture and animal studies indicate that vitamin D has anticancer properties. Thus, it has been hypothesized that this deficiency puts African-Americans at an increased risk of cancer (158
). Although the relationship between vitamin D and cancer has been studied extensively, the results do not support a causative relationship between low vitamin D and an increased prostate cancer risk to date (158
Nutrition is associated with cancer not just through the type of diet but additionally through the effects of obesity. A high calorie intake together with a sedentary lifestyle leads to overweight and obesity. African-Americans have the highest proportion of individuals with a body mass index of >30, which is considered a threshold for being obese (160
). About 37% percent of African-American men fall into this category versus 32% of the entire US male population. Obesity is a risk factor for cancer and has been associated with an increased prostate cancer-specific mortality and treatment failure (161
). Thus, it is possible that the high obesity rate among African-American men has some contribution to the higher disease incidence and mortality among them. Recent studies have investigated the mechanisms of the effects of obesity on cancer and found that dietary factors and obesity may influence prostate tumor biology by modifying gene expression patterns (164
). Gene signatures in prostate tumors may develop in response to nutrition and lifestyle intervention (164
Prostate gland biology is androgen dependent. A racial disparity in tumor androgen receptor expression in men with a localized disease has been observed (166
). Furthermore, several epidemiological studies reported African-American men to have modestly higher blood testosterone levels than European-American men (167
). The biological significance of this observation has since become uncertain because blood male sex hormone levels were not found to be associated with the risk of prostate cancer in prospective studies and in a recent meta-analysis (170
). It was also hypothesized that prostate glands from African-American men may have an increased availability of male sex hormones, increased androgen receptor signaling and an increased potential of cell growth and tumor development. However, when two studies examined prostatic tissue, testosterone and dihydrotestosterone levels were not different between African-Americans and European-Americans (171
). Prostate size is also similar in both groups of men, suggesting that an enhanced androgenic effect is not present in the gland of African-American men (173
). Very recently, two large studies re-examined the question whether male sex hormones are increased in blood samples from African-American males (174
). Both studies did not find elevated testosterone levels in African-American men compared with other population groups (e.g. European-American, Hispanic/Latino, Asian-American men). Instead, it was discovered that serum estrogen differed significantly by race/ethnicity with the highest levels being detected in African-American men and in a group of men from Tobago (174
). This is of interest because estrogen may induce inflammation-induced oxidative/nitrosative stress in the prostate gland (176
). In addition, a higher proportion of African-American than European-American men may have chronic inflammation in their non-cancerous prostate, as observed in one study (177
). Given that prostatic tissue inflammation and prostatitis are risk factors for prostate cancer (178
), prevalent inflammation in the prostate gland of African-American males may put these men at an increased prostate cancer risk.
Numerous studies have examined the possibility of low penetrance genes contributing to the excessive burden of prostate cancer in African-American men. So far, attempts have failed to identify common genetic variations that are associated with prostate cancer mortality (180
). To date, the best described risk locus for prostate cancer is located at 8q24. This locus confers an increased disease risk in many populations (12
). There is also indication that this locus confers a higher risk for prostate cancer in men of African ancestry than in men of European ancestry (12
). Several additional GWAS-identified prostate cancer susceptibility loci (i.e. 11q13, 17q12, 19q33 and Xp11) have been validated in studies of men with African ancestry (19
). Because of the importance of inflammation in disease development, researchers also evaluated the relationship between prostate cancer and common genetic variations in genes comprising inflammation and host defense pathways. These studies yielded preliminary evidence, suggesting that the low penetrance genetic variability in these pathways may influence cancer risk in African-Americans and other population groups (184
Prostate tumors in African-Americans tend to be more aggressive at diagnosis than they are in European-Americans (22
). This observation generated an interest in understanding the biology of these tumors. One recent study by Powell et al.
addressed this question by analyzing autopsy material from prostates of 1056 African-American and European-American men who did not have a prior diagnosis of prostate cancer. Interestingly, Powell et al.
observed that the cancer prevalence was similar between the two race/ethnicity groups at this subclinical stage. However, amongst the men with detectable prostate tumors, African-American men seemed to have faster growing and more aggressive tumors, when compared with European-American men (137
). Additional research will have to investigate further whether mechanisms related to an increased proliferation, as described in this study, or inhibition of apoptosis, as described by others (192
), may promote the enhanced growth of tumors in African-American men. Epidermal growth factor receptor signaling is antiapoptotic and promotes cell proliferation by mechanisms including MAPK, PI3K/Akt and nuclear factor kappa-β activation. Furthermore, this oncogene and candidate drug target is critical in the progression to an androgen-independent disease and therefore has been widely studied in respect to advanced prostate cancer (193
). Notably, the receptor was found to be more commonly expressed in tumors from African-American patients when compared with European-American patients (194
). These studies suggest that epidermal growth factor receptor perhaps contributes to apoptosis inhibition and enhanced proliferation in prostate tumors from African-American patients as well as possibly increasing the odds of disease recurrence.
Epigenetic DNA alterations, which include DNA methylation changes are present in a greater fraction of prostate tumors than any other of the known genetic defects (195
). Changes in DNA methylation are amongst the earliest somatic changes that can be detected in cancerous lesions of the prostate and occur at the stage of proliferative inflammatory atrophy, a precursor lesion in human prostate carcinogenesis. Increased DNA methylation can lead to numerous downstream effects including inactivation of tumor suppressor genes like PTEN
or a loss of protection against reactive chemical species. The latter typically occurs in response to hypermethylation of GSTP1
, which is observed in 90% of prostate cancers (195
). Given the importance of epigenetic DNA alterations in contributing to prostate cancer, the occurrence of DNA hypermethylation in tumors from African-American men has been evaluated. In three studies, a pattern emerged consistent with increased DNA hypermethylation in African-American tumors when compared with similar-stage tumors from European-American men (196
). Currently, it is unknown what mechanisms may lead to race/ethnic differences in promoter DNA hypermethylation and whether this pattern is induced by environmental exposures, intrinsic differences in tumor biology or a combination of the two.
Several research groups have investigated the occurrence of harmful chromosomal alterations in prostate tumors, comparing tumors from African-Americans with tumors from European-Americans. Two studies analyzed tumors from the two patient groups using the same platform (199
), whereas one study compared their analysis of African-American tumors with previously published data from European-Americans (201
). The first study analyzing 16 tumors from each patient group did not observe significant differences in chromosomal aberrations between the patients (199
). The second study reported several differences consistent with distinct genomic aberrations in African-American tumors at chromosomal sites that encode oncogenes (e.g. ETV1
) and tumor suppressor genes (e.g. PTEN
). The third and most recent study evaluated genomic alterations in both a discovery and validation cohort to describe chromosomal aberrations whose occurrence is most distinct between African-American and European-American tumors. The data from this study revealed common genomic alterations specific to African-American tumors that may specifically target immune response genes (200
). Recurrent genomic rearrangements like TMPRSS2
are signature mutations of many human prostate tumors and have important biological and clinical implications (202
). Two studies examined the frequency of these recurrent gene fusions in European, European-American, Chinese, Japanese and African-American prostate cancer patients. Although common in European and European-American patients (in ~50% of patients), these mutations were less frequent in African-American patients, as assessed in one study, and rather uncommon in patients from Asia (2–15%), as found in both studies (203
). This pattern is not restricted to TMPRSS2
rearrangements, but rather evidence supports that inactivation of the PTEN tumor suppressor may follow the same trend (203
). The observations raise the possibility that prostate tumors in Asian populations arise from pathogenic mechanisms that are different from Western populations, which could affect disease aggressiveness. Thus, prostate tumor biology may display an unexpected global heterogeneity between men of European, African and Asian descent.
Gene expression profiling is a hypothesis-generating instrument that allows researchers to examine the phenotypic diversity of tumors. This technique can be very advantageous in exploring tumor biological differences in health disparity research. Using differential display analysis, a novel prostate-specific gene, PCGEM1
, was discovered that had a cell growth-promoting function (205
was mapped to chromosome 2q32 and was shown to be overexpressed in prostate tumors. Further analyses revealed that this gene acts as a non-coding RNA and is most highly expressed in prostate tumors of African-American patients (206
). Although further research is needed, this candidate gene may have important oncogenic functions in prostate cancer biology, particular in respect to the African-American population. Our group and others have used genome-wide gene expression profiling to investigate candidate differences in tumor biology between African-American and European-American prostate cancer patients (69
). Analyzing macrodissected tumors and cultured prostate cancer epithelial cells from African-American and European-American patients, Wallace et al.
and Timofeeva et al.
found consistent gene expression differences between the two patient groups. Notably, several known metastasis-promoting genes, including AMFR
, were more highly expressed in tumors from African-Americans than European-Americans. The two tumor studies by Wallace et al.
and Reams et al.
made another important observation. In agreement with the findings by Rose et al.
), their data pointed to significant differences in tumor immunobiology and inflammation pathways between African-American and European-American patients. Moreover, an interferon γ signature was found to be prominent in tumors from African-American patients (69
). This particular signature appears to be identical to previously identified interferon-related gene signatures that are induced by both tumor–stroma interactions and resistance to DNA damage (208
). Interestingly, the interferon-related signatures in these studies were all found to be associated with metastasis and poor disease outcome. Furthermore, while additional research is required, it is possible that the presence of the interferon-related signature in prostate tumors may also suppress T-cell cytotoxicity directed against cancer cells by mechanisms that may include upregulation of the interferon-response gene, indolamine-2,3-dioxygenase (). We think that tumor-induced mechanisms, environmental stimuli and ancestry-driven intrinsic factors are candidate exposures that induce the interferon-related gene signature in prostate tumors.
Fig. 2. Potential origin and effects of the interferon-related gene signature in tumor biology. Tumor-induced mechanisms, environmental stimuli and/or ancestry-driven intrinsic factors are candidate exposures that induce the interferon-related gene signature (more ...)
In summary, various studies examined the relative contribution of genetic and tumor biological factors to the excess burden of prostate cancer among African-American men. There is good evidence that variations in cancer susceptibility loci by genetic ancestry may contribute to population differences in disease occurrence. Other studies reported consistent differences in tumor markers and tumor biology between African-American and European-American patients. Whether any of these differences are causatively linked to the increased disease aggressiveness of African-American tumors is uncertain and will need further research. Other observations suggest that a low-grade chronic inflammation in the non-cancerous and cancerous prostate gland is more prevalent in African-American men (177
). This condition could be related to environmental factors, tumor microenvironmental factors, immunobiological factors related to ancestry or a combination of these factors.